Pentaerythrite derivatives, the production and use thereof and intermediate products for the synthesis of the same

ABSTRACT

The invention relates to novel compounds derived from pentaerythrite compounds of formula (XII) and (XVI), which can be used as pharmaceutically active substances, specially in the treatment of cardiac and circulatory diseases.

This application is a 371 of PCT/DE98/01635 filed Jun. 11, 1998.

SCOPE OF THE INVENTION

The invention presented here relates to new pentaerythritol derivatives,their preparation and use and intermediates for synthesis of the same,which are used in particular as pharmaceutical products.

KNOWN TECHNICAL BACKGROUND

Organic nitrates such as glycerol trinitrate (GTN) (Murrel, Lancet: 80,113, 151 (1879)), pentaerythrityl tetranitrate (PETN) (Risemann et al.,Circulation, Vol. XVII, 22 (1958), U.S. Pat. No. 2,370,437),isosorbitol-5-mononitrate (ISMN) (DE-OS-22 21 080, DE-OS-27 51 934,DE-OS-30 28 873, DE-PS-29 03 927, DE-OS-31 02 947, DE-OS-31 24 410,EP-A1-045 076, EP-A1-057 847, EP-A1-059 664, EP-A1-064 194, EP-A1-067964, EP-A1-143 507, U.S. Pat. Nos. 3,886,186, 4,065,488, 4,417,065,4,431,829), isosorbitol dinitrate (ISDN) (L. Goldberg, Acta Physiolog.Scand. 15, 173 (1948)), propatyl nitrate (Médard, Mem. Poudres 35: 113(1953)), trolnitrate (FR-PS-984 523) or nicorandil (U.S. Pat. No.4,200,640) and similar compounds are vasodilators, some of which havebeen used for many decades for the selective treatment of anginapectoris and ischaemic heart disease (IHK) with a very wide therapeuticapplication (Nitrangin®, Pentalong®, Monolong®, etc.). Otherpentaerythrityl nitrates and their preparation have also been described(Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363; Camp et al., J. Am.Chem. Soc. 77 (1955), 751). Organic nitrates of a more recent type suchas for example SPM 3672 the ethyl ester of(N-[3-nitratopivaloyl]-L-cysteine) (U.S. Pat. No. 5,284,872) and itsderivatives are intended to have comparable and improved pharmacologicalefficacy when used in the areas mentioned above. Furthermore, thepreparation of 3-nitryloxy-2,2-bis-(nitryloxymethyl)propionic acid andits methyl ester (Nec. Chem. Prum. (1978), 28 (2), 84) has also beendisclosed. The galenic processing of organic nitrates to givepharmaceutical preparations for the treatment of angina pectoris orischaemic heart disease is generally well recognised. It is performedusing methods of operation and rules which are generally familiar to aperson skilled in the pharmaceutical field, wherein the choice oftechnologies to be used and the galenic auxiliary agents to be used aregoverned in the first instance by the active substance to be processed.In this case questions relating to its chemico-physical properties, inparticular the explosive properties which are known to be associatedwith organic nitrates, which requires the use of special safetyprecautions and special processing technologies, the form of applicationchosen, the period of activity required and the avoidance ofmedicament/auxiliary agent incompatibilities are of particularimportance. When using medicaments for angina pectoris or ischaemicheart disease, peroral, parenteral, sublingual or transdermalapplication in the form of tablets, dragees, capsules, solutions, spraysor patches has been described in particular (DD-A5-293 492, DE-AS-26 23800, DE-OS-33 25 652, DE-OS-33 28 094, DE-PS-40 07 705, DE-OS-40 38 203,JP application 59/10513 (1982)). In addition to use as a nitrosingsubstance which has been disclosed for many years, their use for thetreatment and prevention of illnesses which are caused by pathologicallyelevated concentrations of sulfur-containing amino acids in the bodyfluids has also been described. These conditions, caused by congenitalor acquired defects in the metabolism of these amino acids and which arecharacterised by elevated blood and urine concentrations of said aminoacids (homocystinurea), are combined under the expressionhomocystinanaemia (WO-A1-92/18002). The use of specific organic nitratesas endothelial protective agents (DE-A1-44 10 997) and as agents for thetreatment of erectile disfunction (WO-A1-96/32118) has been describedrecently. Furthermore, it is known that 3-amino-1,2,4-oxadiazol-5-onesare suitable as proactive drugs for hydroxyguanidines (Rehse et al.Arch. Pharm. Pharm. Med. Chem. 329, 535 (1996)). On the one hand, thecurrently disclosed organic nitrates (esters of nitric acid) areassociated with a number of therapeutic disadvantages. Thus, forinstance, so-called nitrate tolerance is observed; i.e. the decrease inthe effect of nitrate at high dosage or when administering nitrates witha long-term effect. Side effects such as headaches, nausea, dizziness,feeling weak, reddening of the skin and the risk of a large drop inblood pressure with reflectorial tachycardia have also been demonstrated(Mutschler, Arzneimittelwirkungen, Wissenschaftliche VerlagsgesellschaftmbH, Stuttgart, 1991). On the other hand, PETN has a number ofoutstanding properties as an active substance which is the reason forthe preferred use of this compound as a pharmaceutical product ascompared with other organic nitrates, wherein however restrictedbioavailability of this active substance has been observed (set ofmonographs “Pentaerythrityltetranitrat” Dr. Dietrich Steinkopff Verlag,Darmstadt, 1994 to 1995). Lipophilic organic nitrates are generallyactive for only a short time due to a relatively rapid metabolicdegradation to give less active or inactive biotransformation products(Bonn, “Pharmakokinetik organischer Nitrate” in“Pentaerythrityltetranitrat”, Dr. Dietrich Steinkopff Verlag, Darmstadt,1995).

DESCRIPTION OF THE INVENTION

The object of the invention is to provide new compounds derived frompentaerythritol with pharmacologically advantageous effects.

The object of the invention is achieved by the new compounds of theformulae (I) and (III)

(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR¹)_(o)(COR¹)_(p)  (I)

(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR³)_(o)(COR³)_(p)  (III)

wherein R¹ represents a group of the formula (II),

and R³ represents a group of the formula (IV)

R² represents a C₁ to C₂₀ alkyl group, in particular methyl, ethyl,n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, benzyl,cyclohexylmethyl, 4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl,3-phenylpropyl, 3-cyclohexylpropyl, 3-phthalimidylpropyl,1-naphthylmethyl, cinnamyl, 5-ethoxycarbonylbutyl, 3-aminopropyl,—(CH₂)₃CH(NHCOCH₃)COOH, —(CH₂)₃CH(NHCOCH₃)COOCH₃, or 1,6-hexane-bis andm to p are integers, for which the following is true: m+n+o+p=4, m≧1 ando and/or p≧1. Compounds in which R² represents n-butyl, n-pentyl,n-hexyl, benzyl, 2-phenylether, 3-phenylpropyl, 3-phthalimidylpropyl or5-ethyoxycarbonylbutyl are preferred.

The starting compounds for synthesising compounds of the formulae (I)and (III) are pentaerythritol or its nitrates, i.e. pentaerythritylmononitrate (PEMN), pentaerythrityl dinitrate (PEDN), pentaerythyrityltrinitrate (PETriN) and pentaerythrityl tetranitrate (PETN), which aresynthetically available in good yields in a manner known per se(Simecek, Coll. Czech. Chem. Comm. 27 (1962), 363; Camp et al., J. Am.Chem. Soc. 77 (1955), 751). The compounds PEMN, PEDN and PETriN areconverted into the corresponding tri-, di- or monocarboxylic acids bycomplete or partial oxidation of any hydroxymethyl groups present, andthe corresponding derivatives with nitroxy, hydroxyl and carboxylfunctions are optionally obtained from these by partial hydrazinolysisof the corresponding nitrate function. The formation of compounds of theformulae (I) and (III) is performed by methods of synthesis andprocedures which are familiar to a person skilled in the art, forexample by known ester or amide-forming reactions. Compounds of theformula (IV.1), (FIG. 1), are used as starting materials which are alsorequired and the synthesis of these is described in Rehse et al; Arch.Pharm. Pharm. Med. Chem 329, 535 (1996), wherein reference is now madeto the disclosures in this publication, and in which in addition one ortwo hydrogen atoms in the amino group may be replaced by a suitableleaving group, and also compounds of the formula (V),

in which R² is defined in the same way as for formula (I) and R⁴represents H or a suitable leaving group, which are obtainable in goodyield from compounds of the formula (IV.1) via the reaction scheme shownin FIG. 1.

Compounds of the formula (V)

in which R² is defined in the same way as given for formula (I) and R⁴represents H, a C₁ to C₆ alkanoyl group, salicyloyl or acetylsalicyloyl,are independent embodiments of the invention. Compounds in which R²represents n-butyl, n-pentyl, n-hexyl, benzyl, 2-phenylethyl,3-phenylpropyl, 3-phthalimidylpropyl or 5-ethoxycarbonylbutyl arepreferred. Furthermore, compounds in which R⁴ represents salicyloyl oracetylsalicyloyl and compounds in which R² represents n-butyl, n-pentyl,n-hexyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 3-phthalimidylpropyl or5-ethoxycarbonylbutyl and R⁴ represents salicyloyl or acetylsalicyloylare also preferred.

Compounds of the formula (VI) may also be used to achieve the object ofthe invention,

(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR⁵)_(o)(COR⁵)_(p)  (VI)

in which R⁵ is (2-carboxyphenyl)oxy or (2-alkoxycarbonylphenyl)oxy and mto p are integers, and: m+n+o+p=4, m≧1 and o and/or p≧1, furthermorecompounds of the formula (VII),

(HOCH₂)_(q)(O₂NOCH₂)_(r)C(CH₂OR⁶)_(s)  (VII)

in which R⁶ is salicyloyl or acetylsalicyloyl and q to s are integers,and:

q+r+s=4and r and s are ≧1,

furthermore compounds of the formula (VIII),

(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR⁷)_(o)(COR⁷)_(p)  (VIII)

in which R⁷ is a group of the formula (IX)

R⁸ and R⁹, independently, represent a C₁ to C₆ alkyl group or togetherrepresent a C₁ to C₆ alkylene group, R¹⁰ represents OH, NHR⁸R⁹, C₁ to C₆alkoxy, (2-carboxyphenyl)oxy, (2-alkoxycarbonylphenyl)oxy,(1-carboxymethyl-2-dialkylamino)ethoxy,(1-carboxymethyl-2-trialkylammonium)ethoxy,(1-alkoxycarbonylmethyl-2-dialkylamino)ethoxy,(1-alkoxycarbonylmethyl-2-trialkylammonium)ethoxy, and m to p areintegers, and:

m+n+o+p=4,m≧1 and o and/or p≧1.

A particular embodiment of the present invention is compounds of theformula (X),

in which R⁸ to R¹⁰ are defined in the same way as for formula (IX) andR¹¹ represents NO₂, and compounds of the formula (XI) derived therefrom

in which R¹² also represents a C₁ to C₆ alkyl, in particular methyl,ethyl or n-propyl group, and X represents a group capable of forming ananion, which does not have to be present if the group COR¹⁰ has theability to form internal salts. Compounds of the formula (XII)

of the formula (XIII),

and of the formula (XIV),

in which R¹³ represents H or a C₁ to C₆ alkyl group are particularlypreferred.

Compounds of the formula (XV) in particular contribute to achieving theobject of the invention,

(HOCH₂)_(q)(O₂NOCH₂)_(r)C(CH₂OR¹⁴)_(s)  (XV)

in which R¹⁴ represents the acyl group from a compound of the formula(X) to (XIV), in which R¹¹ also may represent H, a C₁ to C₆ alkanoylgroup, salicyloyl or acetylsalicyloyl or —CO—CH₂—CH(OH)—CH₂—NR⁸R⁹, and qto s are integers, and: q+r+s=4 and r and s are ≧1, in particularcompounds of the formula (XVI),

and those of the formula (XVII),

Depending on the conditions of reaction and the starting materials, theend product is obtained either as a free acid or base, as a basic oracid addition salt or a betaine, each of which lie within the scope ofthe invention. Thus, acidic, basic, neutral or mixed salts and hydratesmay be obtained. On the one hand, each of the salts may be convertedinto the free acid or base by using corresponding agents or byion-exchange in a manner known per se. On the other hand, the free acidsor bases obtained may form salts with organic or inorganic bases oracids. When preparing base addition salts, bases are used in particularwhich form suitable therapeutically acceptable salts.

These bases are for example hydroxides or hydrides of the alkali andalkaline-earth metals, ammonia and amines. When preparing acid additionsalts, those acids are preferably used which form suitabletherapeutically acceptable salts. These types of acids are for example,hydrohalic, sulfonic, phosphoric, nitric and perchloric acids,furthermore aliphatic, acyclic, aromatic, heterocyclic carboxylic orsulfonic acids such as formic, acetic, propionic, succinic, glycolic,lactic, malic, tartaric, citric, gluconic, sugar, glucuronic, ascorbic,maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, p-aminobenzoic,anthranilic, p-hydroxybenzoic, salicylic, acetylsalicylic,p-aminosalicylic, embonic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, ethylenesulfonic, halobenzenesulfonic,toluenesulfonic, naphthylsulfonic or sulfanilic acids and amino acidssuch as for example methionine, tryptophane, lysine or arginine. Theseand other salts of the new compound (sic) may be used as agents forpurifying the free acids or bases which are obtained. Salts of the acidsor bases may be produced and isolated from solutions, and then the freeacid or base may be recovered from a fresh salt solution in a purercondition. As a result of the relationship between the new compounds intheir free form and as their salts, these salts also lie within thescope of the invention. Some of the new compounds may be present asoptical isomers or racemates, depending on the choice of startingmaterials and the method used, or if they contain at least twoasymmetric carbon atoms they may also be present as an isomeric mixture(racemate mixture). The isomeric mixture obtained (racemate mixture) maybe separated into pure racemates with the assistance of chromatographyor fractional crystallisation to give two stereoisomers (diastereomers).The racemates obtained may be separated using methods known per se, suchas by recrystallising from an optically active solvent, by usingmicroorganisms, by reacting with optically active agents to producecompounds which can be separated or by separating on the basis of thedifferent solubilities of the diastereoisomers. Suitable opticallyactive agents are the L- and D-forms of tartaric, di-o-toluyltartaric,malic, mandelic, gluconic, sugar, glucuronic, camphorsulfonic, quinineor binaphthylphosphoric acids. The more active portion of the two mirrorimage isomers is preferably isolated. The starting materials are knownor, if they are intended to be new, can be obtained by methods known perse. At the same time the use of pharmacologically acceptable derivativesof all the previously mentioned compounds is possible. In particular,useful addition compounds, salts or enzymatically or hydrolyticallydecomposable compounds such as esters, amides, hydrazides, which areobtained e.g. by N-amination (DD-B1-230 865 and DD-A3-240 818) of thecorresponding amino compounds, hydrazinium salts and similar represent,if not mentioned above, possible variations.

Compounds according to the invention may be used clinically as such oras part of a pharmaceutical preparation, as an individual activesubstance in combination with each other or with known heart/circulationor vascular treatments, for example combined with ACE inhibitors,antiarteriosclerotic agents, antihypertensive agents, beta-blockers,cholesterol reducers, diuretics, calcium antagonists, coronary dilators,lipid reducers, peripheral vasodilators, phosphodiesterases, inparticular —(V)—, or thrombocyte aggregation inhibitors or othersubstances also used as treatment for heart/circulation conditions. Theprovision of pharmaceutical preparations is performed using methods andrules which are generally familiar to a person skilled in thepharmaceutical field wherein the choice of technology to be used and thegalenic auxiliary agents to be used are governed in the first instanceby the active substance being processed. Here matters relating to itschemico-physical properties, the form of application selected, theduration of activity required, the location of action and avoidance ofmedicament/auxiliary substance incompatibilities are of particularimportance. The person skilled in the art therefore has to select theform of medicament, the auxiliary agents and the method of preparationusing known substance and process parameters in a manner which istrivial per se. The relevant form of medicament should be designed insuch a way that it contains the particular active substance in an amountwhich produces therapeutic levels in the plasma and enables the dailydose to be divided into one to two units for controlled release systemsand into up to ten individual doses in other types of medicament.Continuous application using long term infusion is also suitable. Toproduce endothelial protective effects, long lasting therapeutic levelsin the blood are generally striven for. According to the invention thecompounds mentioned may be applied in particular orally, intravenously,parenterally, sublingually or transdermally. The particular medicamentpreparation is preferably provided in liquid or solid form. Solutions,in particular for the preparation of drops, injections or aerosolsprays, furthermore suspensions, emulsions, syrups, tablets, film-coatedtablets, dragees, capsules, pellets, powders, pastilles, implants,suppositories, creams, gels, salves, patches or other transdermalsystems are suitable for this purpose. The pharmaceutical preparationscontain conventional galenic organic or inorganic supports and auxiliarysubstances which should themselves be chemically inert towards theparticular active substances. Chemical derivatisation during applicationto support materials is also included. This applies in particular to theproduction of adducts with sugar derivatives such as croscarmeloses orcyclodextrins. Suitable pharmaceutical auxiliary substances are, withoutbeing restricted thereto, water, salt solutions, alcohols, plant oils,polyethylene glycols, gelatines, lactoses, amyloses, magnesium stearate,talcum, highly dispersed silicon dioxide, paraffin, fatty acid mono- anddiglycerides, cellulose derivatives, polyvinylpyrrolidone and the like.The preparation may be sterilised and if required may have added theretoauxiliary substances such as fillers, binders, lubricants, mould releaseagents, intestinal lubricants, decomposing agents, moisture retainers,adsorption agents or antidisintegrants, preservatives, stabilisers,emulsifiers, solvent promoters, salt to alter the osmotic pressure,buffer solutions, dyes, fragrances, flavourings or sweeteners. A personskilled in the pharmaceutical art is able to avoid medicament/auxiliaryagent incompatibilities by basing his choice on the relevant substanceparameters.

Surprisingly, it was found that compounds according to the inventionhave the required properties. In addition they are characterised by anoptimised NO liberation, e.g. due to their differentiated concentrationof reductive biotransforming NO precursor groups or an improvedmulti-phase NO liberation and, depending on the ultimate application,increased lipophilicity or hydrophilicity and also by lowering thepharmacodynamic threshold, reduced endothelial increase in the plasma,pronounced thrombocyte aggregation inhibition by thrombocyte-activegroups and, even in sub-haemodynamic dosage, by endothelial-protectiveeffects. Particularly advantageous is the fact that compounds accordingto the invention are characterised by good penetration of physiologicalmembranes. Furthermore it was found that in particular the compoundsderived from carboxyl compounds and their salts or quaternary ammoniumcompounds can be processed to give pharmaceutical preparations in theform of sprays and injection solutions. Compounds used in accordancewith the invention, surprisingly, show in functional tests on isolatedblood vessels (rabbit aorta) a high vaso-dilatory property with improvedbioavailability and increased hydrophilicity as well as facilitatedbiotransformation to give the final metabolites, wherein these finalmetabolites are generally very well tolerated or are compounds which arenormally present in the body. They are characterised, surprisingly, asstrongly hydrophilic, nitrate vasodilators which have a long half-lifeand improved bioavailability as compared with lipophilic nitrates. Itwas surprising that compounds according to the invention could on theone hand trigger the strong pharmacodynamic effects which are typical oflipophilic organic nitrates without their pronounced short term effectand on the other hand have the characteristic long term effect of morehydrophilic organic nitrates, that is they combine the advantages oflipophilic and hydrophilic organic nitrates within the compounds usedwithout exhibiting any of their pharmacodynamic disadvantages. Thususing the invention described, improved and considerably extendedtherapeutic opportunities are opened up and pathological conditions suchas heart and circulatory illnesses, in particular coronary heartdisease, vascular stenoses and bleeding problems in the peripheralarteries, hypertonia, micro and macroangiopathies within the context ofdiabetes mellitus, arteriosclerosis and the secondary illnessesresulting therefrom, furthermore erectile disfunction, elevated internaleye pressure, uterine spasms, menopausal problems, etc. can be treated.Some of the compounds described above may be characterised, on the basisof their chemico-physical properties, as explosives, which may alsoenable their use as such. A person skilled in the art is able to selectcompounds for this purpose on the basis of known test processes. Incontrast to that, however, a number of substances according to theinvention do not have this property or this property is only weaklyexpressed so that these compounds are characterised by the absence ofthe disintegrant properties which are typical of organic nitrates whileat the same time being characterised by the retention of and improvementin pharmacological effects due to a particularly simple and reliablemethod of preparation, handling and further processing. In additioncompounds described in the present invention are useful startingcompounds and intermediates for the preparation of chemical derivativeswhich may themselves be used as pharmaceutical active substances. Theexamples given below are intended to explain the invention in moredetail without however restricting its scope.

EXAMPLES Example 1

158 g (0.5 mol) of pentaerythrityl tetranitrate (PETN) were dissolved ina mixture of 300 ml of dioxan and 300 ml of ethanol at boiling point anddifferent amounts of aqueous hydrazine hydrate solution (1.5-4 mol) wereadded thereto in portions over the course of 1 hour. Then the reactionmixture was boiled under reflux for a further 2.5 hours. Nitrogen,ammonia and nitrogen oxides evolved during the reaction. After reaction,the solvent was evaporated off at 15 mm Hg and the residue, if required,was shaken up several times with 100 ml portions of water until thevolume of the oil layer could no longer be reduced during shaking. Theaqueous extracts (A) were combined and the remaining oily layer wasdissolved in twice the volume of ethanol. The white precipitate of PETN,which may have settled out, was filtered off after 24 hours: it had am.p. of 132° C. After recrystallising twice from acetone its m.p. hadincreased to 141° C. Ethanol was evaporated from the filtrate at 15 mmHg. The viscous, oily residue consisted of pentaerythrityl trinitrate(PETriN).

Example 2

The combined aqueous extracts A were shaken up 3 times with ether andthe ether was evaporated out of the etheral layer isolated from theaqueous layer B after drying over anhydrous Na₂SO₄. The very viscous,oily residue after evaporation was identified as crude pentaerythrityldinitrate (PEDN). The aqueous fraction B which, in addition topentaerythrityl mononitrate (PEMN) and pentaerythrityl denitrationproducts, contained mainly hydrazine nitrite, was acidified successivelywith 2N H₂SO₄ until the production of gas could be heard (N₂, N₂O, NO,N₃H), then concentrated by evaporation at 20 mm Hg until the separationof a solid product started to occur and then the ether was removed. Thecrystalline substance with a m.p. of 62° C. which remained afterevaporation of the ether was identified as crude PEMN. After washingwith cold chloroform and recrystallising from chloroform the plateletsobtained had a m.p. of 79° C. The extraction residue was evaporated todryness at 10 mm Hg and the residue was stirred into a small amount ofwater. The white crystals which were filtered off, and which had a m.p.of 260° C. after recrystallisation from the same amount by weight ofwater, were identified as pure pentaerythritol.

Example 3

In order to purify the crude substances PETriN and PEDN, these wereconverted into the relevant acetates and alcoholised to give the pureproducts after recrystallisation from ethanol. To 135.5 g (0.5 mol) ofcrude PETriN [or 56.5 g (0.25 mol) of PEDN] a mixture of 50 ml of aceticanhydride and 20 ml of acetyl chloride were added in portions withcooling and stirring. The mixture which solidifed after reaction wasstirred into 50 ml of ethanol and separated under suction twice. Thecolourless crystals of pentaerytrityl trinitrate acetate (PETriNAc) witha m.p. of 85 to 86° C. had a m.p. of 89° C. after recrystallising twicefrom ethanol. The yield of pure product was 121 g (77%). Pentaerythrityldinitrate diacetate (PEDNAc) also formed colourless crystals with a m.p.of 42 to 43° C. which increased to 47° C. after recrystallisation twicefrom ethanol. The yield of pure product was 56 g (72%). 104.4 g (0.3mol) of PETriNAc or 51.7 g (0.15 mol) of PEDNAc were dissolved in 400 mlof hot ethanol, a solution of 1.5 g of NaOH in 50 ml of ethanol wasadded and the azeotropic mixture of ethanol/ethyl acetate (K_(p) 71.8°C./760 mm) was distilled off. After completion of ethyl acetateformation, a further 1.5 g of NaOH and 50 ml of ethanol were added andagain fractionated until further ethyl acetate no longer passed over.Then the ethanol was evaporated off at 15 mm Hg and the residue in thecase of the substance PETriN, was shaken up 3 times with 20 ml of waterand in the case of the substance PEDN was stirred into 100 ml of waterand ether removed 3 times. After drying under vacuum or removing theether respectively, the pure substances PETriN and PEDN were obtained ascolourless viscous liquids, which were dried under vacuum over P₂O₅ foranalysis.

Example 4

PETriN was also processed in such a way that it was stirred into 100 mlof water after washing with water and then allowed to stand until thenext day at a temperature which was no higher than 20° C. Colourlesscrystals were obtained, stable in air, with a m.p. of 32° C., containing2.14±0.05% of water according to the Karl-Fischer reaction and 2.15% ofwater according to vacuum drying, corresponding to a hydrate with thecomposition C₅H₉O₁₀N₃.1/3H₂O.

Example 5

PETriN is prepared by nitration of pentaerythritol with HNO₃ (95%strength) in the presence of urea.

Example 6

PEDN and PEMN are prepared from PETriN by hyrazinolysis (4 mol NH₂NH₂(50% strength)) with subsequent column chromatographic separation of the1:1 mixture.

Example 7

0.0074 mol of KMnO₄ is added in portions with vigorous stirring to asolution of 0.0037 mol of pentaeythrityl trinitrate (PETriN), 5.5 ml ofbenzene, 9 ml of water and 0.15 ml of Aliquate® 336. When addition iscomplete, the temperature is held at 15° C. for 2 hours. Then aqueoushydrogen sulfite solution is added to the mixture, the mixture isacidified with H₂SO₄ and the benzene layer is isolated. After removingthe solvent, 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid (Tri-PA)is obtained as a solid residue which is recrystallised several timesfrom methylene chloride (yield: 72%).

Example 8

1.0 g (0.0061 mol) of 2,2-bis(hydroxymethyl)malonic acid is added to amixture of 2.5 g of 95 (%) strength HNO₃, a spatula tip-full of urea and10 ml of water, with stirring and ice-cooling. After 10 min 2.5 g of 94%strength H₂SO₄ are added dropwise and the mixture is stirred for anotherhour at 0° C. The organic layer is separated and evaporated down.2,2-bis(nitryloxymethyl)malonic acid is obtained as a viscous oil as theresidue, which is purified column chromatographically.

Yield: 45%. Elemental analysis: (C: corresponds, H: corresponds, N:corresponds).

Example 9 2-carboxy-2-nitryloxymethylmalonic acid

To a mixture cooled to 0° C. of 2.5 g of 95 (%) strength HNO₃, aspatula-full of urea and 10 ml of water is added with stirring andice-cooling, 1.0 g (0.004 mol) of carboxy-2-hydroxymethylmalonic acid.After 10 min 2.5 g of 94% strength H₂SO₄ are added dropwise withstirring and stirring is continued for another hour at 0° C. The organiclayer is isolated and evaporated down.2-carboxy-2-nitryloxymethylmalonic acid is obtained as the residue as aviscous oil which is purified column chromatographically.

Yield: 30%. Elemental analysis: (C: corresponds, H: corresponds, N:corresponds).

Example 10

0.001 mol of bis-MA is azeotropically esterified with 0.0011 mol of4-butyl-3-hydroxy-1,2,4-oxydiazole-5-one in the presence of benzene andcatalytic amounts of H₂SO₄ (yield: 60%).

Example 11

0.001 mol of bis-MA is azeotropically esterified with 0.0011 mol of4-(2-phenylethyl)-3-hydroxyl-1,2,4-oxadiazole-5-one in the presence ofbenzene and catalytic amounts of H₂SO₄ (yield: 53%).

Example 12

0.001 mol of CN-MA is azeotropically esterified with 0.0022 mol of4-butyl-3-hydroxyl-1,2,4-oxadiazole-5-one in the presence of benzene andcatalytic amounts of H₂SO₄ (yield: 45%).

Example 13

0.01 mol of 4-chloro-3-hydroxybutanoic acid is converted into4-chloro-3-nitroxybutanoic acid with 3 times the amount of HNO₃/H₂SO₄(nitrating acid) (yield: 76%).

Example 14

Aqueous trimethylamine solution is added to 0.005 mol of4-chloro-3-nitroxybutanoic acid in a sealable vessel, the vessel issealed and the resulting mixture is heated at 80° C. for 1 hour. Aftercooling, the solution is evaporated down, cooled and the mixture left tocrystallise with cooling. 3-nitryloxy-4-trimethylammoniumbutyrylchloride (salt) is obtained (yield: 71%).

Example 15

0.001 mol of the compound according to example 14 are azeotropicallyesterified with 0.0011 mol of PETriN in the presence of benzene andcatalytic amounts of H₂SO₄ (yield: 37%).

Example 16 a) 3-Nitryloxy-2,2-bis(nitryloxymethyl)propionyl chloride

1 g (3.5 mmol) of Tri-PA is heated with 5.3 mmol of thionyl chloride for1.5 hours under reflux: the excess thionyl chloride is distilled off,first on a water bath and then under vacuum. The residue is taken up indiethylether and washed rapidly with a little ice-water. The organicphase is isolated, dried over sodium sulfate and the solvent isevaporated under vacuum. The oily3-nitryloxy-2,2-bis(nitryloxymethyl)propionyl chloride (tri-PACl)produced is pure enough for use in further reactions. Yield: 75%.

b) 2,2-bis(nitryloxymethyl)malonyl chloride and2-chlorocarbonyl-2-nitryloxymethylmalonyl dichloride

The acid chlorides of the compounds 2,2-bis(nitryloxymethyl)malonic acid(bis-MA) and 2-carboxy-2-nitryloxymethylmalonic acid (CN-MA) areobtained in the same way. To prepare 2,2-bis(nitryloxymethyl)malonyldichloride (bis-MACl), double the amount of thionyl chloride is used andto prepare 2-chlorocarbonyl-2-nitryloxymethylmalonyl dichloride(CN-MACl), 3 times the amount of thionyl chloride is used. Yield: 70 and45% respectively.

c) Methyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate

1 ml of thionyl chloride and 1 drop of dry DMF are added to 7 mmol oftri-PA and stirred with the exclusion of moisture for 20 min at roomtemperature. Then excess thionyl chloride is distilled off and 10 ml ofdry methanol is added to the reaction mixture cooled to 0° C. After 30min the mixture is diluted with 30 ml of water and extracted 5 timeswith diethylether. Column chromatographic purification (hexane: ethylacetate=2:1) of the crude product obtained after evaporating off thesolvent produced methyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionateas colourless crystals. Yield: 44%.

C₆H₉N₃O₁₁, M=299.14; m.p.=66° C.; R_(f)=0.65 (silica gel, hexane: ethylacetate=1:1).

d) Ethyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate

10.5 mmol of ethanol, 20 mg of toluenesulfonic acid and 30 ml ofchloroform are added to 1 g (3.5 mmol) of tri-PA and heated for 12 hourson a water separator under reflux. The chloroform phase is washed withaqueous bicarbonate solution and with water, the solvent is evaporatedoff under vacuum and the residue is purified column chromatographically.Ethyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate is obtained ascolourless oil. Yield: 85%.

e) Butyl 3-Nitryloxy-2,2-bis(nitryloxymethyl)propionate

1 ml of n-butanol is dissolved in 5 ml of pyridine and 0.5 g (1.7 mmol)of tri-PACl) dissolved in 5 ml of tetrahydrofuran is added thereto withice-cooling. The mixture is heated for 1 hour on a water bath. Themixture is then poured into 50 ml of ice-water and carefully neutralisedwith hydrochloric acid. The oily ester which separates out is taken upin diethylether, washed with aqueous sodium carbonate solution andwater, the organic phase is dried over sodium sulfate and the solvent isevaporated off under vacuum. Column chromatographic purification of theresidue produces butyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionate asa colourless oil. Yield: 69%.

f) The esters of the carboxylic acids bis-MA and CN-MA are obtained inthe same way by doubling (in the case of bis-MA) and tripling (in thecase of CN-MA) respectively the amount of reagent added. g) Diethyl2,2-bis(nitryloxymethyl)malonate

0.015 mol of diethyl 2,2-bis(hydroxymethyl)malonate are slowly added toa solution of 90 g of degassed 100% nitric acid at −5° C. under a streamof air. The reaction mixture is thoroughly ventilated for a further 120min at −5° C. and then poured into ice-water. The aqueous phase isde-etherified twice, the organic phase is washed with 10% strengthhydrogen carbonate solution and with water, dried over sodium sulfateand the solvent evaporated off under vacuum. The residue is separated ona chromatography column. Yield: 94%. R_(f)=0.52 (silica gel, hexane:ethyl acetate=2:1); ¹H NMR (300 MHz, CDCl₃): corresponds; ¹³C NMR (75MHz, CDCl₃): corresponds.

h) 3-nitryloxy-2,2-bis(nitryloxymethyl)propionamide

1 g (3.4 mmol) of tri-PACl is dissolved in 25 ml of dioxan and excessconcentrated ammonia solution is added thereto. After 30 min the mixtureis poured into 100 ml of ice-water and slightly acidified with dilutehydrochloric acid. The oily2,2-bis(nitryloxymethyl)-3-nitryloxypropionamide which separates out ispurified column chromatographically. Yield: 65%.

i) 3-nitryloxy-2,2-bis(nitryloxymethyl)propionamide

1 ml of thionyl chloride and 1 drop of dry DMF are added to 7 mmol oftri-PA and the mixture is stirred with the exclusion of moisture for 20min at room temperature. Then 3 ml of cold concentrated NH₃ solution areadded to the reaction mixture and the solution is allowed to cool toroom temperature. After extracting the aqueous phase with diethyl ether5 times and removing the solvent, an oily crude product is obtained fromwhich 3-nitryloxy-2,2-bis(nitryloxymethyl)propionamide is isolated ascolourless crystals by means of column chromatography (hexane:ethylacetate=1:1). Yield: 32%; C₅H₈N₄O₁₀, M=284.13; R_(f)=0.52 (silica gel,hexane:ethyl acetate=1:1). m.p. 71-72° C. (CHCl₃).

j) 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid N-benzylamide

1 g (3.5 mmol) of methyl 3-nitryloxy-2,2-bis(nitryloxymethyl)propionateis heated with 3 ml of benzylamine and 100 ml of ammonium chloride for 3hours at 130° C., cooled, taken up in 50 ml of chloroform and washed insequence with water, dilute hydrochloric acid, aqueous bicarbonatesolution and again with water. The crude product obtained afterevaporating off the solvent is purified column chromatographically.3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid N-benzylamide isobtained as a colourless oil. Yield: 73%.

k) 3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid hydrazide

1 g (3.5 mmol) of methyl 2,2-bis(nitryloxymethyl)-3-nitryloxypropionateis heated with excess aqueous hydrazine hydrochloride solution for 5hours on a water bath. The mixture is poured onto ice and slightlyacidified with hydrochloric acid. After column chromatographicseparation of the oil which is produced,3-nitryloxy-2,2-bis(nitryloxymethyl)propionic acid hydrazide is obtainedas a colourless oil. Yield: 63%.

l) The amides or hydrazides of the carboxylic acids bis-MA and CN-MA areproduced in the same way by doubling and tripling respectively thereagents.

The compounds described above under a) to 1) may be used as startingmaterials and intermediates for further reactions.

Example 17

3.4 mmol of L-carnitine hydrochloride are esterified with 1 g (3.4 mmol)of tri-PACl in 25 ml of dioxan. After 30 min, the mixture is poured into100 ml of ice-water and slightly acidified with dilute hydrochloricacid. The oily product which separates out is purified columnchromatographically. Yield: 40%.

Example 18 3-trimethylammonium-2-nitryloxypropanecarboxylate

1 g of carnitine hydrochloride is added to 8 ml of 70% strength nitricacid cooled to 0° C. After adding 5.5 ml of 96% strength sulfuric acidat 0° C., the mixture is stirred at room temperature for 1 hour andpoured onto 50 ml of ice-water. After neutralisation (pH 7.0) with 10%strength caustic soda solution, the mixture is evaporated to drynessunder vacuum, the residue is extracted twice with ethanol, the alcoholis evaporated off and the crude product obtained is purified columnchromatographically (silica gel, methanol) (yellowy oil). Yield 56%.

Example 19

Testing the pharmacological effect of the compounds:

a) The test is performed with cultivated cells (RFL-6-fibroplasts,LLC-PK1-epithelial cells), which are known as a model for characterisingthe activity and tolerance profiles of NO donors (Bennet et al., J.Pharmacol. Ther. 250 (1989), 316; Schröder et al., J. Appl. Cardiol. 2(1987), 301; J. Pharmacol. Exp. Ther. 245 (1988), 413; NaunynSchmiedeberg's Arch. Pharimacol. 342 (199), 616; J. Pharmacol. Exp.Ther. 262 (1992), 298; Adv. Drug. Res., 28 (1996), 253). Theintracellular accumulation of cGMP as a parameter for nitrate effect andbioactivation is measured using a radio-immuno assay.

b) The thrombocyte aggregation and thrombus production inhibiting effectof the compounds is determined using Rehse et al.'s method (Arch. Pharm.324, 301-305 (1991); Arch. Pharm. Pharm. Med. Chem. 329, 535 (1996)),which is established as a model for describing anticoagulant andantithrombotic properties.

c) The endothelial protective effect of the compounds is determinedusing Noack and Kojda's known method (DE-A1-44 10 997).

d) The vasodilating properties were tested in experiments on isolatedaortal rings from rabbits (Hüsgen, Noack, Kojda: Int Confer. “Mediatorsin the cardiovascular system”, p.9, Malta 2-5.6.1994), by suspendingthese in organ baths and stimulating them with vasoconstrictors such asphenylephrin. After establishing a stable, smooth muscular tone, theeffect of the tone is determined by cumulative concentration/effectcurves for the vasodilators mentioned above. For this, increasingconcentrations of between 1 nM and 10 μM of the vasodilator are added tothe organ bath buffer, wherein the system is not washed out between thevarious fractions. As a result of adding the substances, there was astepwise increase in the contraction in the presence of thevasoconstrictor in all the aorta rings. The extent of relaxation isexpressed as a percentage of the contraction still remaining (residualcontraction) for the particular active substance concentration. The halfpeak active concentration EC50 gives the strength of activity and isdetermined as the pD2 value (concentration in logM).

Example 20

A tablet had the composition:

Active substance(s) x mg Lactose DAB 10 137 mg Potato starch DAB 10 80mg Gelatine DAB 10 3 mg Talcum DAB 10 22 mg Magnesium stearate DAB 10 5mg Silicon dioxide, highly dispersed DAB 10 6 mg Active substance(s): a)Compound according to example 10 20 mg b) Compound according to example10 50 mg c) Compound according to example 10 80 mg d) Compound accordingto example 11 20 mg e) Compound according to example 11 50 mg f)Compound according to example 11 80 mg g) Compound according to example12 20 mg h) Compound according to example 12 50 mg i) Compound accordingto example 12 80 mg j) Compound according to example 14 20 mg k)Compound according to example 14 50 mg l) Compound according to example14 80 mg m) Compound according to example 15 20 mg n) Compound accordingto example 15 50 mg o) Compound according to example 15 80 mg p)Compound according to example 17 50 mg q) Compound according to example7 30 mg Compound according to example 14 50 mg r) Compound according toexample 7 30 mg Compound according to example 15 50 mg s) Compoundaccording to example 14 30 mg Pentaerythrityl tetranitrate 50 mg t)Compound according to example 15 30 mg Pentaerythrityl tetranitrate 50mg u) Compound according to example 10 50 mg Acetylsalicylic acid 50 mgv) Compound according to example 12 50 mg Acetylsalicylic acid 50 mg w)Compound according to example 14 50 mg Acetylsalicylic acid 50 mg x)Compound according to example 15 50 mg Acetylsalicylic acid 50 mg y)Compound according to example 14 50 mg Captopril 25 mg z) Compoundaccording to example 15 50 mg Captopril 25 mg

What is claimed is:
 1. A compound having a formula (I)(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR¹)_(o)(COR¹)_(p)  (I) in which R¹represents a group of formula (II),

R² represents a C₁ to C₂₀ alkyl group, benzyl, cyclohexylmethyl,4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl, 3-phenylpropyl,3-cyclohexylpropyl, 3-phthalimidylpropyl, 1-naphthylmethyl, cinnamyl,5-ethoxy-carbonylbutyl, 3-aminopropyl, —(CH₂)₃CH (NHCOCH₃)COOH,—(CH₂)₃CH (NHCOCH₃)COOCH₃, or 1,6-hexane-bis-, and m to p are integers,and m+n+o+p=4, m≧1, o and/or p≧1, and their therapeutically acceptablesalts.
 2. A compound having a formula (III),(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR³)_(o)(COR³)_(p)  (III) in which R³represents a group of formula (IV)

R² represents a C₁ to C₂₀ alkyl group, benzyl, cyclohexylmethyl,4-chlorobenzyl, 4-nitrobenzyl, 2-phenylethyl, 3-phenylpropyl,3-cyclohexylpropyl, 3-phthalimidylpropyl, 1-naphthylmethyl, cinnamyl,5-ethoxy-carbonylbutyl, 3-aminopropyl, —(CH₂)₃CH(NHCOCH₃)COOH,—(CH₂)₃CH(NHCOCH₃)COOCH₃, or 1,6-hexane-bis-, and m to p are integers,and m+n+o+p=4, m≧1, o and/or p≧1, and their therapeutically acceptablesalts.
 3. A compound having a formula (VI),(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR⁵)_(o)(COR⁵)_(p)  (VI) in which R⁵ is(2-carboxyphenyl)oxy or (2alkoxycarbonyl-phenyl)oxy and m to p areintegers, and m+n+o+p=4, m≧1, o and/or p≧1, and their therapeuticallyacceptable salts.
 4. A compound having a formula (VIII),(O₂NOCH₂)_(m)C(CH₂OH)_(n)(CH₂COR⁷)_(o)(COR⁷)_(p)  (VIII) in which R⁷ isa group of formula (IX),

R⁸ and R⁹, independently, represent a C₁ to C₆ alkyl group or togetherrepresent a C₁ to C₆ alkylene group, R¹⁰ represents OH, NHR⁸R⁹, a C₁ toC₆ alkoxy group, (2-carboxyphenyl)oxy, (2-alkoxycarbonylphenyl)oxy,(1-carboxymethyl-2-dialkylamino)ethoxy,(1-carboxymethyl-2-trialkylammonium)ethoxy,(1-alkoxycarbonylmethyl-2-dialkylamino)ethoxy,(1-alkoxycarbonylmethyl-2-trialkylammonium)ethoxy, and m to p areintegers and m+n+o+p=4, m≧1, o and/or p≧1, and their therapeuticallyacceptable salts, quaternary salts, or betaines.
 5. A pharmaceuticalagent containing one or more compounds of claim 1, 2, 3, or
 4. 6. Apharmaceutical agent according to claim 5 further comprising otheractive agents for treating heart/circulation or vascular illnessesselected from the group consisting of ACE inhibitors,antiartheriosclerotic agents, antihypertensive agents, beta-blockers,cholesterol reducers, diuretics, calcium antagonists, coronary dilators,lipid reducers, peripheral vasodilators, phosphodiesterase inhibitors,and thrombocyte aggregation inhibitors.
 7. The compound of claim 1wherein the C₁ to C₂₀ alkyl group is selected from the group consistingof methyl, ethyl, n-propyl, i-propyl, n-butyl, n-pentyl, n-hexyl, andn-octyl.
 8. The compound of claim 2 wherein the C₁ to C₂₀ alkyl group isselected from the group consisting of methyl, ethyl, n-propyl, i-propyl,n-butyl, n-pentyl, n-hexyl, and n-octyl.